Basics
Description
There are 4 main types of systemic amyloidosis: �
- AL amyloidosis (formerly called primary amyloidosis): Plasma cell dyscrasia results in proliferation of monoclonal immunoglobulin light chains.
- AA amyloidosis (formerly called secondary amyloidosis, or reactive systemic amyloidosis): Chronic inflammatory conditions result in production of acute phase reactants.
- Hereditary systemic amyloidosis (HSA): Liver produces mutant transthyretin (TTR).
- Senile systemic amyloidosis (SSA): Amyloid is formed from normal wild-type TTR.
Epidemiology
Incidence
- AL amyloidosis is the most common type of systemic and cardiac amyloidosis in developed countries.
- AA amyloidosis is very uncommon.
- Hereditary amyloidosis is transmitted via an autosomal-dominant mode of inheritance and can lead to cardiomyopathy in 25% of patients.
Prevalence
Senile amyloidosis is extremely rare at age <60 yr old; but the prevalence of amyloid fibrils in myocardium on autopsy is between 25% and 36% in those >80 yr old (much fewer have clinical manifestations); there is a male predominance. �
Risk Factors
- AL: Plasma cell dyscrasia: Multiple myeloma; lymphoma; macroglobulinemia
- AA: Chronic inflammatory conditions: Chronic infection; rheumatoid arthritis and other rheumatologic disease; inflammatory bowel disease
- Hereditary: Inherited mutations in TTR gene
- Senile: Male sex (almost exclusively affects men); age ≥70 yr old
- Other: End-stage renal disease (ESRD) on hemodialysis
Genetics
- Hereditary systemic amyloidosis:
- There are >100 point mutations in the TTR gene.
- Inheritance is autosomal dominant with high penetrance.
- Four percent of African Americans are heterozygous for Val122Ile TTR mutation, likely the most common hereditary amyloid cardiomyopathy. 23% of African Americans with cardiac amyloidosis have this mutation.
Pathophysiology
Amyloid fibrils infiltrate the extracellular space of the ventricles, atria, and valves. Over time, the myocardium becomes thickened and rubbery, resulting in restrictive cardiomyopathy, systolic dysfunction, and arrhythmias. �
Etiology
Amyloidogenic proteins come from many sources: �
- AL: Excess monoclonal immunoglobulin light chains (whole or part of variable VL domain) produced by plasma cell dyscrasia
- AA: Acute phase reactants produced by chronic inflammatory conditions
- Hereditary: Mutant TTR, a serum carrier of thyroxin and retinol, produced by the liver. Rarely, the etiology is mutant apolipoprotein A-I, lysozyme, fibrinogen α-chain, or other.
- Senile: Wild-type TTR.
- Other: Amyloidosis can result from accumulation of β2-microglobulin in end-stage renal disease patients on hemodialysis, which does not clear this protein (mainly affects the joints; rarely affects the heart)
Associated Conditions
- AL: Renal involvement is common (proteinuria; renal failure); neuropathy (peripheral and autonomic; carpal tunnel); hepatomegaly; macroglossia; lone cardiac involvement is very rare (<5%).
- AA: Mainly renal failure and hepatomegaly; cardiac involvement is extremely rare.
- Hereditary: Nephropathy, severe neuropathy, and/or cardiomyopathy (the heart is most prominently involved).
- Senile: Mainly cardiac involvement; carpal tunnel syndrome.
Diagnosis
- Rapidly progressive CHF: Dyspnea, peripheral edema; ascites; anasarca; pleural effusions
- Chest pain: Both nonanginal and anginal (often due to microvascular disease with impaired myocardial flow reserve in the absence of epicardial coronary disease)
- Syncope: Due to autonomic neuropathy and/or reduced preload with diastolic dysfunction
- Low BP and orthostasis: Due to autonomic dysfunction
- Atrial arrhythmias (10-15% of patients)
- Thromboembolic phenomena: Due to atrial fibrillation and atrial standstill; more common with AL amyloidosis
- Neurological findings: Painful sensory neuropathy (10-20%) and autonomic neuropathy; carpal tunnel syndrome (up to 20%)
- Periorbital purpura and macroglossia are highly specific for AL amyloidosis.
- Family history of amyloidosis or heart failure is important for determining heritable etiology.
Tests
EKG: �
- Low voltage despite echocardiographic LV wall thickening in 47-70% of cases.
- Pseudo-infarction pattern (no infarct by echo) with QS waves in contiguous leads is common: Anterior (36%); inferior (12%); lateral (14%).
- Atrial fibrillation is common (10-15% of patients).
- Premature ventricular contractions, ventricular arrhythmias, sick sinus syndrome, AV block, and prolonged QT may be seen.
Lab
Lab
- Fibril typing is key for management and prognosis.
- With biopsy-proven amyloidosis and well-defined plasma cell dyscrasia (eg, multiple myeloma or Waldenstr �m's macroglobulinemia), further diagnostic testing for fibril type is not necessary.
- Without well-defined plasma cell dyscrasia, test serum and urine protein electrophoresis (SPEP & UPEP) and immunofixation; serum free light chain assay; consider bone marrow biopsy.
- Presence of monoclonal protein alone is not enough to diagnose AL amyloidosis unless immunofluorescence reveals monoclonal light chains in the amyloid deposits on biopsy. Test for genetic mutations in TTR (or ApoA1).
Lab
Serum immunoglobulin free light chain assay is an automated immunoassay that quantifies circulating amyloid fibril precursor proteins; it is a good serial test to assess response to chemotherapy in AL amyloidosis. AA amyloidosis has a similar assay to monitor precursor proteins. �
Imaging
Lab
- Echo with Doppler imaging:
- Thickened LV wall in the absence of HTN, and in the presence of low EKG voltage should raise suspicion for infiltrative cardiomyopathy such as amyloidosis.
- Severe LV wall thickening, mostly septal and free wall, with small ventricular cavity. RV is also thickened.
- Thickened walls have granular or sparkling pattern due to increased echogenicity (formerly considered pathognomonic; harmonics may eliminate sparkling pattern).
- Both atria are usually dilated (27-50%) due to atrial pressure overload.
- Thickened interatrial septum, found in a minority of cases, is specific for amyloid.
- Thickened atrioventricular valves. Valvular regurgitation, and less commonly, stenosis, can occur.
- A small pericardial effusion is often present.
- Diastolic dysfunction; progressive infiltration is associated with worsening diastolic function.
- Systolic dysfunction is uncommon until late stage, and overall is absent in 75% of cases.
- Thrombus may be seen in either the atria or ventricles in 27% of cases.
- CXR:
- May show cardiomegaly, pleural effusions, and pulmonary vascular congestion
Lab
- Cardiac MRI:
- Circumferential late gadolinium enhancement (LGE), mostly in ventricular subendocardial and mid-mural regions
- Elevated T1 and T2 relaxation times
- Increased interatrial and interventricular septum thickness
- Nuclear imaging with radiolabeled technetium has poor sensitivity and is not recommended.
Surgery
- Biopsy:
- For definitive diagnosis, endomyocardial biopsy stained with Congo red reveals amorphous pink deposits under light microscopy, with apple-green birefringence under polarized microscopy.
- Extracardiac biopsy (eg, fat pad biopsy for AL amyloidosis; rectal biopsy for senile amyloidosis) may be sufficient for diagnosis with the right clinical picture.
- Right heart catheterization: Elevated biventricular diastolic pressures, with rapid equalization of diastolic pressures; pressure tracings reveal characteristic "dip-and-plateau,"� or, "square root sign."�
Pathological Findings
- Histology:
- Amorphous hyaline deposits throughout the extracellular myocardium.
- Characteristic fibrillar pattern of extracellular amyloid deposits can be seen by electron microscopy.
- Gross:
- Thickened ventricles, valves, and interatrial septum
Differential Diagnosis
In patients with echocardiographic LV thickening, consider: Hypertensive heart disease; sarcoidosis; hemochromatosis; hypertrophic cardiomyopathy; athlete's heart; Fabry disease; Pompe disease �
Treatment
Medication
- Treatment of AL amyloidosis:
- Melphalan and dexamethasone: Monthly oral dosing is better tolerated, but has poor response rate
- 2nd-line chemotherapy for AL: Lenalidomide and dexamethasone; cyclophosphamide, thalidomide, and dexamethasone; vincristine, Adriamycin, and dexamethasone.
- Treatment of AA amyloidosis: Inhibitors of tumor necrosis factor and interleukin-1.
- Hereditary and senile amyloidosis: No pharmacotherapy is available, other than supportive care for CHF.
Additional Treatment
General Measures
- Treat underlying disease process (for AL and AA) to reduce production of amyloid fibril precursor proteins.
- Supportive care for CHF.
- Medication choices may differ from usual CHF management due to restrictive physiology and autonomic neuropathy. The mainstay is diuretic use; high doses may be needed if patient has nephrotic syndrome/hypoalbuminemia.
- Organ transplantation (liver for hereditary; stem cell for AL; heart) may be indicated in selected patients.
Surgery
- AL amyloidosis: Heart transplantation followed by stem cell transplantation and chemotherapy may result in long-term remission in cases with predominantly cardiac involvement
- Hereditary amyloidosis: Combined liver and heart transplant in selected cases. Liver transplant has good outcomes for young fit patients with Met30 amyloidogenic mutation; older non-Met30 mutants can have paradoxical increased rate of TTR amyloid protein deposition.
- 5-yr survival after heart transplant for cardiac amyloidosis is 38%, vs. 67% among patients with cardiac transplant for other reasons.
- Pacemakers are indicated for advanced heart block. Dual chamber device may improve atrial filling; no data on biventricular pacing
- Prevention of sudden cardiac death: Implantable cardioverter-defibrillator (ICD) may be considered in selected patients. However, limited prognosis, lack of cardiac reserve, and electromechanical dissociation may make ICD therapy ineffective.
- LV assist devices: Not systematically studied in amyloidosis
In-Patient Considerations
Initial-Stabilization
May need large doses of diuretics, especially with renal involvement/nephrotic syndrome. �
Ongoing Care
Prognosis
- AL amyloidosis: Median survival is 13 mo (4 mo if heart failure is present and underlying cause is not treated). Death in systemic AL amyloidosis with cardiac involvement is due to heart failure or arrhythmia in >50% of cases. With chemotherapy, a sustained ≥50% reduction in aberrant monoclonal immunoglobulin light chains (assessed serum assay) correlates with enhanced survival.
- AA amyloidosis: Median survival is 25 mo if left untreated. A dramatic improvement in survival occurs with treatment of the underlying inflammatory disorder. Organ dysfunction may be reversed.
- Hereditary amyloidosis: Median survival is 70 mo if untreated.
- Senile amyloidosis: Slowly progressive despite older age and greater myocardial infiltration compared with AL amyloidosis. Median survival is 75 mo; death is usually due to heart failure/arrhythmias.
- Factors that correlate with poor prognosis: A small persistent elevation in serum troponin; increased ventricular wall thickness on echo; poor NYHA functional class; and ventricular ectopy (couplets on Holter correlate with sudden death)
- Troponin T and I, and N-terminal (NT)-proBNP elevations at time of diagnosis suggest poor prognosis. Survival at time of diagnosis is 6 or 8 mo with detectable troponin T or I, vs. 22 or 21 mo without detectable troponin T or I, respectively.
Additional Reading
1Selvanayagam �JB, Hawkins �PN, Myerson �SG. Evaluation and management of the cardiac amyloidosis. J Am Coll Cardiol. 2007;50: 2101-2110. �[View Abstract]
Codes
ICD9
- 277.30 Amyloidosis, unspecified
- 277.39 Other amyloidosis
- 425.7 Nutritional and metabolic cardiomyopathy
SNOMED
- 17602002 amyloidosis (disorder)
- 274945004 AA amyloidosis (disorder)
- 23132008 AL amyloidosis (disorder)
- 89449005 systemic amyloidosis (disorder)
- 237877004 senile systemic amyloidosis (disorder)
Clinical Pearls
Suspect cardiac amyloidosis in heart failure patients with echo findings of thickened LV in the absence of HTN, and with low voltage on EKG. �